Download Trazodone for the treatment of fibromyalgia

Morillas-Arques et al. BMC Musculoskeletal Disorders 2010, 11:204
http://www.biomedcentral.com/1471-2474/11/204
RESEARCH ARTICLE
Open Access
Trazodone for the treatment of fibromyalgia:
an open-label, 12-week study
Piedad Morillas-Arques, Carmen Ma Rodriguez-Lopez, Rocio Molina-Barea, Fernando Rico-Villademoros,
Elena P Calandre*
Abstract
Background: Despite its frequent use as a hypnotic, trazodone has not been systematically assessed in
fibromyalgia patients. In the present study have we evaluated the potential effectiveness and tolerability of
trazodone in the treatment of fibromyalgia.
Methods: A flexible dose of trazodone (50-300 mg/day), was administered to 66 fibromyalgia patients for 12
weeks. The primary outcome measure was the Pittsburgh Sleep Quality Index (PSQI). Secondary outcome measures
included the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI), the Hospital Anxiety
and Depression Scale (HADS), the Brief Pain Inventory (BPI), the Short-Form Health Survey (SF-36), and the Patients’
Global Improvement Scale (PGI). Trazodone’s emergent adverse reactions were recorded. Data were analyzed with
repeated measures one-way ANOVA and paired Student’s t test.
Results: Trazodone markedly improved sleep quality, with large effect sizes in total PSQI score as well on sleep
quality, sleep duration and sleep efficiency. Significant improvement, although with moderate effect sizes, were
also observed in total FIQ scores, anxiety and depression scores (both HADS and BDI), and pain interference with
daily activities. Unexpectedly, the most frequent and severe side effect associated with trazodone in our sample
was tachycardia, which was reported by 14 (21.2%) patients.
Conclusions: In doses higher than those usually prescribed as hypnotic, the utility of trazodone in fibromyalgia
management surpasses its hypnotic activity. However, the emergence of tachycardia should be closely monitored.
Trial registration: This trial has been registered with ClinicalTrials.gov number NCT-00791739.
Background
Disturbed sleep is a prominent feature of fibromyalgia
symptomatology and has been proposed as one of the
core symptoms that should be systematically assessed in
clinical trials for the treatment of fibromyalgia [1]. Trazodone is an old second-generation antidepressant with
strong sedative activity, widely used as a hypnotic drug
in sub-therapeutic antidepressant doses of 100 mg or
less, although the evidence of the efficacy of this drug in
treating insomnia in non-depressed patients is very limited [2]. Despite this relative paucity of data, low-dose
trazodone is frequently used in fibromyalgia management to improve sleep quality [3] and is currently
* Correspondence: [email protected]
Instituto de Neurociencias y Centro de Investigaciones Biomédicas,
Universidad de Granada, Granada, Spain
recommended for this purpose by the American Pain
Society [4].
However, the efficacy of trazodone for fibromyalgia,
either as a hypnotic or as an antidepressant, has not
been adequately investigated. Only one, study published
in abstract form, has evaluated the polysomnographic
and clinical effects of trazodone in thirteen women with
fibromyalgia [5]. The authors of the study stated that a
two-month treatment with trazodone increased slowwave sleep and reduced alpha activity but did not
improve pain or psychological distress; however, they
did not mention the daily dosage of trazodone that was
used. The increase in slow-wave sleep induced by trazodone, in comparison with placebo treatment, has also
been demostrated in two randomized clinical trials in
healthy subjects [6,7]
© 2010 Morillas-Arques et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Morillas-Arques et al. BMC Musculoskeletal Disorders 2010, 11:204
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Symptoms of depression and anxiety are frequently
found in fibromyalgia patients and trazodone has antidepressant and anxiolytic properties [8] in doses higher
than those usually employed to treat insomnia (i.e.
50-100 mg at bedtime) [9]. Thus, it could be useful to
treat other symptoms of fibromyalgia in addition to
insomnia. The present study was undertaken with the
following objectives:
1. To evaluate the effectiveness of flexibly dosed trazodone in patients with fibromyalgia in improving:
- sleep quality as measured by the Pittsburgh Sleep
Quality Index
- fibromyalgia overall symptomatology as measured by
the FIQ total score
- anxiety, depression, and quality of life.
2. To assess trazodone’s tolerability in the range of
administered doses.
Methods
The study included patients who had been diagnosed
with fibromyalgia according to the American College of
Rheumatology Criteria [10], were willing to discontinue
their current prescribed treatment, and were referred to
our unit by their physicians (general practitioners, rheumatologists and physicians from pain-management
clinics). Patients who had been previously treated with
trazodone but had not improved or did not tolerate the
drug were excluded. Every patient gave informed consent to participation in the study, which was approved
by the Ethics Committee of the University of Granada.
The trial registration number was NCT-00791739.
Before starting the study the patients were required to
withdraw from any current chronic pharmacological
medication prescribed for fibromyalgia; no discontinuation was required for non-pharmacological treatments,
herbal remedies, or drugs used on a p.r.n. basis.
After a patient-tailored washout period, trazodone was
administered at a starting dose of 25 mg at bedtime and
increased in 25 to 50 mg/day increments at 2-week
intervals if the patient reported little or no clinical
improvement. The dosage increase was maintained until
a relevant clinical benefit was reached, according to the
investigator’s judgment, or side effects appeared.
According to the trazodone package insert [11], the
maximum allowed dosage was fixed at 400 mg daily.
Patients were seen at baseline and at 2, 4, 6, 8, 10 and
12 weeks. Clinical investigators, all of whom were physicians, were the responsible for drug dispensation, dosage
adjustments and monitoring for adverse drug reactions.
The primary outcome measure used was the Spanishvalidated Pittsburgh Sleep Quality Index (PSQI) [12].
Secondary efficacy outcome measures included the following spanish-validated scales: the Fibromyalgia Impact
Questionnaire (FIQ) [13], the Beck Depression Inventory
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(BDI) [14], the Hospital Anxiety and Depression Scale
(HADS) [15], the Brief Pain Inventory (BPI) [16], the
Short-Form Health Survey (SF-36) [17], and the
Patients’ Global Improvement Scale (PGI). Scales were
administered at baseline and at weeks 6 and 12, with
the exception of the SF-36 which was administered only
at baseline and at week 12. Trazodone emergent side
effects were recorded by the physician at each patient’s
visit by means of an open-ended question; patients were
also instructed to phone the attending physician if they
believed that they were experiencing any drug-related
side effect.
The intention-to-treat (ITT) sample included those
patients who started trazodone and had at least a postbaseline assessment. Data were analyzed with repeated
measures ANOVA and with paired Student’s t test in
the case of SF-36. Effect sizes were calculated according
to Cohen’s formula.
Results
As shown in Figure 1, a total of 72 patients willing to participate were screened. However, 6 of them were unable
to complete the washout period. Therefore 66 patients,
61 women and 5 men aged from 22 to 70 years (48 ±
9.7), began trazodone treatment. Fifty nine patients completed at least a one post-baseline assessment and constituted the ITT sample. Twenty three patients (35%)
withdrew from the study at different times during the
evaluation period, 12 of them due to treatment-emergent
side effects, and 11 were lost to follow up. Among the 66
patients who started trazodone, 33 (59%) had been prescribed benzodiazepines, zolpidem or zopiclone on a
daily basis but still complained of sleep difficulties. Final
doses of trazodone varied from 50 to 300 mg/day, with a
mean value of 200 ± 70 mg/day.
Efficacy measure data are shown in Tables 1, 2 and 3.
Trazodone had a significant effect on sleep parameters
with the largest effect sizes in sleep quality, duration
and efficacy at week 12 (Table 1). Improvement in sleep
quality, as measured by the differences in PSQI total
scores between week 12 and baseline was not related
with the final dose of trazodone.
The FIQ total scores, whose baseline values ranged
from 33 to 99, decreased significantly, with moderate to
large effect sizes in fatigue, morning tiredness, stiffness
and anxiety at week 12 (Table 2). There was not a clearcut relationship between trazodone dose and differences
between FIQ total scores at week 12 and at baseline;
however, patients receiving >200 mg/day of trazodone
improved significantly more than those receiving doses
of 100 mg or less (mean FIQ scores differences of 11.6 ±
2.7 and 4.1 ± 1.9 respectively, p = 0.029).
Both depression and anxiety scores were significantly
lower at week 12, especially among patients with
Morillas-Arques et al. BMC Musculoskeletal Disorders 2010, 11:204
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under trazodone; 20 (46.5%) reported slight improvement, 8 (18.6%) reported no change, and 7 (16.3%)
reported worsening.
The most frequent side effect of trazodone was tachycardia (N = 14, 21.2% of the total sample), followed by
dry mouth (N = 10, 15.2%), sedation (N = 7, 10.6%), dizziness and lightheadedness (N = 6, 9.1% for each
adverse reaction). Twelve (18.2%) patients withdrew
from the study due to side effects, six (50%) of them
due to tachycardia; all of these patients were receiving
trazodone doses equal to or lower than 150 mg daily.
Figure 1 Patients flow diagram.
clinically relevant depression and/or anxiety at baseline
(Table 3). Similarly to the FIQ findings, the differences
between BDI total scores at week 12 and baseline were
significantly higher in patients receiving >200 mg/day of
trazodone than in those receiving doses of 100 mg or
less (mean scores differences of 8.3 ± 2.2 and 2.1 ± 0.9
respectively, p = 0.015).
Trazodone did not markedly improve pain intensity
but had a significant effect on pain interference with
daily activities at week 12 (Table 3). A moderate
improvement, although with a small effect size, was also
seen in the Mental Component Summary (MCS) of the
SF-36 at week 12.
Among the 43 patients that completed the study, 8
(18.6%) reported to much or very much improvement
Discussion
As expected, trazodone had the greatest impact on sleep
parameters. In addition, although to varying degrees, significant improvements were also observed in general fibromyalgia symptomatology as well as in anxiety and
depression. Branco et al [5] did not find that trazodone
caused changes in psychological profile nor clinical symptoms under trazodone treatment. However, as stated in
the introduction, their abstract did not specify tradozone
dosage. Furthermore, the study lasted only two months
which was probably too short a time period of time too
short to appraise the full efficacy of the drug, since, as the
STAR*D study has demonstrated [18], depressed patients
may need a treatment course longer than 8 weeks to
achieve remission under antidepressant treatment.
The improvement of sleep quality with trazodone was
striking, especially when considering that most patients
previously received benzodiazepines, zolpidem or zopiclone with only limited success. Benzodiazepines, zolpidem, zopiclone and trazodone all increase total sleep
time; the main difference is that trazodone increases
stages 3 and 4 of sleep whereas the other drugs mainly
increase stage 2 of sleep [19,20]. Patients with fibromyalgia show a reduction in the total duration of slow wave
sleep, and intrusion of alfa waves superimposed to the
delta frequency which is characteristic of the slow wave
sleep [21]. Trazodone does not only increase the total
duration of slow wave sleep, but has also demonstrated
to reduce the alpha activity in the sleep of fibromyalgia
patients [5]. It is thus possible that the beneficial effects
of trazodone on sleep quality in our patients could be
due to its differential effects on sleep structure.
Bodily pain, which is the cardinal symptom that defines
fibromyalgia, was only slightly improved with trazodone
administration; however, other relevant symptoms of the
disease such as fatigue, morning tiredness, and stiffness
were alleviated, and there was also a strong beneficial
effect on sleep parameters. This clinical profile likely does
not warrant the use of trazodone use as a single agent in
fibromyalgia treatment at the low-to-medium trazodone
doses evaluated in our study but suggests that it could be
used as an adjunctive agent. Although monotherapy
Morillas-Arques et al. BMC Musculoskeletal Disorders 2010, 11:204
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Table 1 PSQI total and individual scores throughout the study period
Total score (mean ± s.d.)
baseline
week 6
week 12
P (anova)
16.2 ± 3.3
12.9 ± 4.1***
12.1 ± 5.0***
< 0.0001
1.00
1.24
1.78 ± 0.9***
1.64 ± 0.9***
3.6
3.88
2.2 ± 0.9**
1.9 ± 1.1***
0.36
0.73
2.58 ± 0.6
1.98 ± 1.0***
1.75 ± 1.1***
< 0.0001
2.68 ± 0.7
1.00
2.03 ± 1.2***
1.38
1.59 ± 2.2***
< 0.0001
0.93
1.56
2.07 ± 0.6**
2.02 ± 0.7***
0.58
0.68
0.97 ± 1.4*
0.73 ± 1.2**
0.30
0.46
2.02 ± 0.9**
1.98 ± 0.9**
0.38
0.42
ES
Sleep quality (mean ± s.d.)
3.58 ± 0.5
ES
Sleep latency (mean ± s.d.)
2.49 ± 0.8
ES
Sleep duration (mean ± s.d.)
ES
Sleep efficiency (mean ± s.d.)
ES
Sleep disturbance (mean ± s.d.)
2.36 ± 0.5
ES
Sleeping medications (mean ± s.d.)
1.42 ± 1.5
ES
Daytime dysfunction (mean ± s.d.)
2.32 ± 0.8
ES
< 0.0001
< 0.0001
= 0.0001
= 0.0033
= 0.0013
*: p < 0.05, **:p < 0.01, and ***: p < 0.001 in relation to baseline (Dunnett’s post-test)
ES: effect size; bold: moderate and large effect sizes
would be an ideal option for the treatment of fibromyalgia,
this is not possible in many cases. The complexity of fibromyalgia symptomatology has been acknowledged, and a
Symptom Severity Scale for the disease has recently been
included in the new proposal of fibromyalgia diagnostic
criteria the by the American College of Rheumatology
[22]. Patients with a wide range of symptoms frequently
require the use of more than one drug simultaneously,
and the need for the prescription of two or more drugs for
fibromyalgia management has been acknowledged [23]. In
fact, several observational prospective and longitudinal
studies show that prescription drugs use is high among
fibromyalgia patients [24], and that polytherapy is usual,
with a mean range of 2.7 to 3.3 drugs per patient
[22,25,26]. Given its positive effect on sleep quality,
depression and anxiety, and its lack of analgesic activity,
trazodone could be combined with drugs that have analgesic efficacy but with less favourable effects on sleep parameters, such as NSAIDs, tramadol, or duloxetine [27-30].
Decreases in PSQI total scores were not related with
the final dose of trazodone, suggesting that the improvement in sleep quality associated with trazodone
Table 2 Fibromyalgia Impact Questionnaire scores throughout the study period
baseline
week 6
week 12
P (anova)
Total score (mean ± s.d.)
ES
77.5 ± 13.4
70.8 ± 15.8***
0.5
67.9 ± 17.9***
0.72
< 0.0001
Work (mean ± s.d.)
8.15 ± 1.6
7.42 ± 2.0**
7.43 ± 2.1**
= 0.0014
0.46
0.45
7.78 ± 1.7*
7.46 ± 1.9***
0.28
0.47
8.09 ± 2.1*
8.03 ± 2.1*
0.47
0.51
ES
Pain (mean ± s.d.)
8.26 ± 1.7
ES
Fatigue (mean ± s.d.)
8.75 ± 1.4
ES
= 0.0007
= 0.0140
Morning tiredness (mean ± s.d.)
ES
8.86 ± 1.4
7.78 ± 2.4**
0.77
7.72 ± 2.6**
0.81
= 0.0005
Stiffness (mean ± s.d.)
8.04 ± 2.0
7.12 ± 2.8**
6.94 ± 2.8***
= 0.0006
0.46
0.55
7.44 ± 2.7*
7.04 ± 2.7***
0.37
0.58
6.98 ± 2.9
7.06 ± 3.0
0.38
0.35
ES
Anxiety (mean ± s.d.)
8.15 ± 1.9
ES
Depression (mean ± s.d.)
ES
7.94 ± 2.5
*: p < 0.05, **:p < 0.01, and ***:p < 0.001 in relation to baseline (Dunnett’s post-test)
ES: effect size;bold: moderate and large effect sizes
= 0.0010
= 0.0027
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Table 3 Depression, anxiety, pain and quality of life scores throughout the study period
BDI-whole sample (mean ± s.d.)
baseline
week 6
week 12
P (anova)
28.0 ± 10.7
24.9 ± 12.3*
22.5 ± 10.7***
< 0.0001
0.29
0.51
26.9 ± 12.0*
23.3 ± 10.1***
0.45
0.84
11.6 ± 4.8
11.0 ± 5.0**
0.16
0.29
13.6 ± 3.8
12.5 ± 4.2
11.6 ± 4.5**
= 0.0054
13.8 ± 4.2
0.29
13.1 ± 4.7
0.53
12.3 ± 4.9**
= 0.0041
0.17
0.36
13.6 ± 4.3
12.7 ± 4.4**
0.26
0.53
7.00 ± 1.8*
6.95 ± 1.8*
0.29
0.33
7.11 ± 2.2***
6.82 ± 2.6***
< 0.0001
0.66
0.84
28.2 ± 5.2
N.S.
ES
BDI > 18 (N = 41) (mean ± s.d.)
31 ± 9.2
ES
HADS-depression (mean ± s.d.)
12.4 ± 4.9
ES
HADS depression > 7 (N = 43) (mean ± s.d.)
ES
HADS anxiety (mean ± s.d.)
ES
HADS anxiety >7 (N = 47) (mean ± s.d.)
14.5 ± 3.4
ES
BPI: mean pain severity (mean ± s.d.)
7.47 ± 1.6
ES
BPI: pain interference with daily activities (mean ± s.d.)
ES
SF-36: PCS (mean ± s.d.)
8.42 ± 1.7
27.3 ± 4.1
ES
SF-36: MCS (mean ± s.d.)
< 0.0001
= 0.0142
= 0.0061
= 0.0154
-0.22
28.0 ± 11.5
ES
30.7 ± 12.5*
= 0.0383
-0.23
*: p < 0.05, **:p < 0.01, and ***: p < 0.001 in relation to baseline (Dunnett’s post-test)
ES: effect size; bold: moderate and large effect sizes
treatment can be reached with low daily doses of the
drug. In contrast, the highest trazodone doses (i.e., those
higher than 200 mg daily) were associated with more
pronounced decreases both in FIQ and BDI total scores
in some patients. These data seem to indicate that, in
doses similar to those used for the treatment of depression, trazodone could be also useful to treat fibromyalgia
symptomatology.
Among our patients, tachycardia was the most frequent
adverse reaction and the main reason for treatment discontinuation. It was seen at drug doses as low as 50 mg/
day and usually appeared during the first weeks of treatment. Tachycardia is a relatively uncommon side effect
of trazodone [11,31], having been reported in clinical
trials in percentages ranging from 0 to 7% of patients.
This unexpectedly high prevalence of tachycardia in our
sample might be due to the well-known association
between fibromyalgia and autonomic dysfunction, which
has been shown to facilitate increases in heart rate as a
response to different kinds of stimuli [32].
The main limitation of our work was its uncontrolled
and open-label design which may have overestimated
treatment effects. However, the study was conceived as
a preliminary research aiming to evaluate the potential
usefulness of an old drug, widely used but scarcely
investigated, in the management of fibromyalgia. The
12-week duration of the study may be an additional limitation; a longer evaluation period may have been more
appropriate, particularly considering that the open-label
design of the study did not allow us to control for a
potential placebo effect.
The reduction of the sample size due to patients withdrawal may have reduced representativeness of sample
and the generalizability of results. However, since we
used an intent-to-treat approach to the analysis, it does
not seem probable that this fact affected the external
validity of the study in a relevant manner.
The use of an open-ended question to assess emergent
side effects may have underestimate the their actual frequency; this is, however, the standard method of evaluation of adverse reactions in clinical trials, and
unexpected and/or serious side-effects are usually captured by this kind of evaluation. On the other hand, the
use of a checklist could have had the opposite effect, i.e.
to overestimate the frequency of side effects.
Finally, the possibility that the washout period could
have increased patients expectations in relation to trazodone treatment cannot be overlooked. Nevertheless,
washout was essential to avoid side effects due to drug
interactions and its duration was kept as short as possible, not lasting more than four weeks as maximum in
the case of patients heavily polymedicated.
Despite the above-mentioned limitations of the study,
our data suggest that trazodone deserves further evaluation as a potential treatment for fibromyalgia. Additional
studies exploring the efficacy of the drug in doses up to
400 mg/day, with a randomized and controlled design,
would be worthy to be performed in the future.
Morillas-Arques et al. BMC Musculoskeletal Disorders 2010, 11:204
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Conclusion
Despite the limitations of its uncontrolled design, the
results of our study show that trazodone markedly
improves subjective sleep quality in patients with fibromyalgia. The beneficial effects of trazodone seem also to
extend to other symptoms such as anxiety and depressive symptoms. However, its usefulness seems to be limited by its tolerability, tachycardia being a relevant
adverse reaction that should be closely monitorized.
Authors’ contributions
EPC and FRV designed the study, evaluated the results, and wrote the
manuscript. PMA, CMRL and RML did the clinical work. All authors have read
and approved the final manuscript
Page 6 of 6
16.
17.
18.
19.
20.
Competing interests
The authors declare that they have no competing interests.
Received: 9 May 2010 Accepted: 10 September 2010
Published: 10 September 2010
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2474/11/204/prepub
doi:10.1186/1471-2474-11-204
Cite this article as: Morillas-Arques et al.: Trazodone for the treatment of
fibromyalgia: an open-label, 12-week study. BMC Musculoskeletal
Disorders 2010 11:204.